Abstract: Esophageal squamous cell carcinoma (ESCC) predominantly affects African Americans rather than Caucasian Americans at a ratio of about 4:1. African American patients with ESCC have much worse prognosis than their Caucasian counterparts. Therefore it is important to better understand molecular mechanisms of ESCC and develop targeted therapy for this deadly disease in order to reduce racial disparity. Recent NextGen sequencing studies have identified multiple driver mutations in human ESCC among which Nrf2 and Keap1 mutations are known to activate Nrf2 signaling. However, the molecular mechanisms of Nrf2-associated carcinogenesis have not been clearly understood particularly in vivo. Based on our preliminary data, we hypothesize that Nrf2 activation induces esophageal hyperproliferation and hyperkeratosis through the EGFR/PI3K/Akt pathway and metabolic reprogramming. Using the Keap1-/- mouse model of esophageal hyperproliferation and hyperkeratosis, we plan to test our hypothesis with two specific aims: (1) To examine whether Nrf2 activation in Keap1-/- esophagus activates the EGFR/PI3K/Akt pathway and metabolic reprogramming through transcriptional regulation of genes of the EGFR/PI3K/Akt pathway and energy metabolism. (2)To test whether genetic or chemical inhibition of the EGFR/PI3K/Akt pathway or metabolic reprogramming may suppress esophageal phenotype in Keap1-/- mice, and whether inhibition of both events may have synergistic effect. This Pilot Project is aimed to understand the carcinogenic mechanisms of Nrf2 activation in esophageal squamous cell carcinogenesis in vivo. If successful, it will lay down a solid foundation for translational studies on Nrf2-high ESCC and contribute to reduction of cancer health disparity in the African American population.